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Journal or Publication Title: | Journal of the American Society of Nephrology | ||||
Publisher: | American Society of Nephrology | ||||
Volume: | 33 | ||||
Date: | 11 February 2022 | ||||
Institutions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Armin Kurtz Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Richard Warth Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Wolf Hayo Castrop | ||||
Identification Number: |
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Keywords: | epithelial transport physiologyinfertilitymegalinEps15 homology domainproximal tubulegenetic renal diseasemutation | ||||
Dewey Decimal Classification: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine | ||||
Status: | Published | ||||
Refereed: | Yes, this version has been refereed | ||||
Created at the University of Regensburg: | Partially | ||||
Item ID: | 51687 |
Abstract
Background The endocytic reabsorption of proteins in the proximal tubule requires a complex machinery and defects can lead to tubular proteinuria. The precise mechanisms of endocytosis and processing of receptors and cargo are incompletely understood. EHD1 belongs to a family of proteins presumably involved in the scission of intracellular vesicles and in ciliogenesis. However, the relevance of ...

Abstract
Background
The endocytic reabsorption of proteins in the proximal tubule requires a complex machinery and defects can lead to tubular proteinuria. The precise mechanisms of endocytosis and processing of receptors and cargo are incompletely understood. EHD1 belongs to a family of proteins presumably involved in the scission of intracellular vesicles and in ciliogenesis. However, the relevance of EHD1 in human tissues, in particular in the kidney, was unknown.
Methods
Genetic techniques were used in patients with tubular proteinuria and deafness to identify the disease-causing gene. Diagnostic and functional studies were performed in patients and disease models to investigate the pathophysiology.
Results
We identified six individuals (5–33 years) with proteinuria and a high-frequency hearing deficit associated with the homozygous missense variant c.1192C>T (p.R398W) in EHD1. Proteinuria (0.7–2.1 g/d) consisted predominantly of low molecular weight proteins, reflecting impaired renal proximal tubular endocytosis of filtered proteins. Ehd1 knockout and Ehd1R398W/R398W knockin mice also showed a high-frequency hearing deficit and impaired receptor-mediated endocytosis in proximal tubules, and a zebrafish model showed impaired ability to reabsorb low molecular weight dextran. Interestingly, ciliogenesis appeared unaffected in patients and mouse models. In silico structural analysis predicted a destabilizing effect of the R398W variant and possible inference with nucleotide binding leading to impaired EHD1 oligomerization and membrane remodeling ability.
Conclusions
A homozygous missense variant of EHD1 causes a previously unrecognized autosomal recessive disorder characterized by sensorineural deafness and tubular proteinuria. Recessive EHD1 variants should be considered in individuals with hearing impairment, especially if tubular proteinuria is noted.
Metadata last modified: 18 Feb 2022 06:25